Chronic infections have been shown to enhance atherogenicity. However, the association between chronic hepatitis C (HCV) and coronary heart disease (CHD) remains controversial. We examined the risk for CHD events in patients with HCV with an emphasis on the risk of CHD events with active infection. We conducted a retrospective cohort study using the enterprise data warehouse at the University of Arkansas for Medical Sciences. HCV positive and negative patients were identified based on serology, and incident CHD events were studied. Patient characteristics at entry were compared either by the analysis of variance or F test (continuous variables) or by a chi-square test (categorical variables). The joint effect of risk factors for incident CHD was evaluated using logistic regression. A total of 8,251 HCV antibody positive, 1,434 HCV RNA positive, and 14,799 HCV negative patients were identified. Patients with HCV antibody and RNA positivity had a higher incidence of hypertension, diabetes mellitus, obesity, and chronic lung disease, but lower serum cholesterol levels compared with patients who were HCV negative (p <0.001). HCV seropositive patients had a higher incidence of CHD events compared with controls (4.9% vs 3.2%, p <0.001). In the HCV cohort, patients with detectable HCV RNA had a significantly higher incidence of CHD events compared with patients who were only HCV antibody positive with no detectable RNA (5.9% vs 4.7%, p = 0.04). In multivariate logistic regression analyses, both HCV antibody positivity (odds ratio 1.32, 95% confidence interval 1.09 to 1.60, p <0.001) and HCV RNA positivity (odds ratio 1.59, 95% confidence interval 1.13 to 2.26, p <0.001) were independent risk factors for incident CHD events. In conclusion, there is an increased incidence of CHD events in patients with HCV seropositivity and the incidence is much higher in patients with detectable HCV RNA compared with patients with remote infection who are only antibody positive. Lipid profile does not appear to be a good cardiovascular risk stratification tool in patients with HVC.
A large body of evidence has linked chronic infections with atherosclerotic vascular disease. Transmission of infectious pathogens increases the extent of atherosclerosis in experimental animal models. Chronic infections have also been shown to increase the risk of coronary heart disease (CHD) events in humans. However, an association between chronic hepatitis C (HCV) infection and cardiovascular risk has been supported by some, but not other studies. Some studies have even suggested that HCV infection may be protective against atherosclerosis. A recent systematic review suggested that the association between HCV infection and CHD events is inconclusive and needs additional research. Some of the reasons for discrepancy among these studies include the use of different diagnostic criteria for defining chronic HCV infection, small sample sizes, and the use of different end points. In addition, persistent infection with HCV (Antibody (Ab) + and RNA+) was not differentiated from remote HCV infection (Ab+ and RNA−) that was cleared by host antiviral responses or by antiviral therapy. Using a large university-based electronic medical records database, we sought to examine the effect of HCV infection on incident CHD events and to specifically study if patients with a detectable HCV RNA have a higher risk of CHD events.
Methods
We conducted a retrospective cohort study using the enterprise data warehouse at the University of Arkansas for Medical Sciences (UAMS). The data warehouse is funded by the Translational Research Institute at UAMS. The data warehouse is updated monthly and maintains de-identified clinical information of nearly 1 million patients in the UAMS system. Information on patient demographics, International Classification of Diseases (ICD) 9 diagnoses, procedural codes, visit status, laboratory parameters, and discharge disposition is available through the database.
We identified patients with a diagnosis of HCV infection from January 1, 2001, to December 31, 2013. HCV infection was defined as the presence of HCV antibody as detected by enzyme-linked immunosorbent assay or a positive result of a qualitative or quantitative test for HCV RNA by polymerase chain reaction (PCR). Patients were divided into 3 study groups: (a) patients with HCV antibodies by enzyme-linked immunosorbent assay and no detectable HCV RNA by PCR in peripheral blood (Ab+ and RNA−); (b) patients with HCV antibodies and detectable HCV RNA (Ab+ and RNA+); and (c) controls without HCV antibodies or RNA (Ab− and RNA−). The control group consisted of a randomly selected gender-matched sample of HCV negative patients in the database within the study period. We labeled patients in group a as having “remote” HCV infection (previously treated or spontaneous clearance of infection or HCV RNA was never checked) and patients in group b as having “persistent infection”. Patients in group a and b were all positive for HCV antibody, but patients in only group b had positive HCV RNA. For patients in the HCV group, date of diagnosis of HCV (after January 1, 2001) was chosen as the study initiation date. For HCV negative patients, the date of first visit in the UAMS system after January 1, 2001, was chosen as the study initiation date. The date of the last clinical visit since the study initiation date for all patients was selected as the study completion date. Validated ICD 9 codes for hypertension, diabetes mellitus, and chronic obstructive pulmonary disease (COPD) were used for identification of co-morbidities. CHD was defined by the presence of a diagnosis code for any of the following: coronary artery disease, chronic stable angina, unstable angina, or acute myocardial infarction. A CHD event was recorded if a patient had an ICD 9 code for any of the previously mentioned diagnoses since the study initiation period. Patients who had multiple ICD 9 codes for CHD events mentioned previously were counted as 1 CHD event. Obesity was defined as body mass index >29.5 kg/m 2 . A diagnosis of COPD was used as a surrogate marker of smoking as actual smoking data in terms of pack years were not available. Patients in the HCV group who had a diagnosis of CHD (based on the previously mentioned ICD9 code criteria) before their diagnosis of HCV were excluded from the study. Similarly, patients in the control group who had a diagnosis of CHD before the beginning of the study period were excluded.
Demographic data collected included age, gender, and race. Laboratory data collected included HCV antibody status, quantitative HCV RNA by PCR, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, alkaline phosphatase, serum albumin, total bilirubin, international normalized ratio, hemoglobin A1c, and serum creatinine. Patients’ age at the study initiation period was used in the final analysis. Laboratory data available within the first 1 year of study initiation were collected. For patients who had repeat HCV serologies done, the first available HCV RNA PCR result was used for analysis.
Statistical analyses were computed with SAS version 9.4 (SAS Institute, Inc., Cary, North Carolina). Patient characteristics at study initiation were compared among the 3 study groups either by the analysis of variance or F test (continuous characteristics) or by a chi-square test (categorical characteristics). The joint effect of risk factors for incident CHD was evaluated using logistic regression with odds ratios and their 95% confidence intervals reported as the estimate of risk. Differences in odds ratios for CHD among the 3 study HCV groups were also adjusted for all significant main effects and 2-way interactions among the set of CHD risk factors: age, gender, hypertension, COPD, diabetes, and obesity.
Results
Our final cohort consisted of 24,484 patients (8,251 HCV antibody positive, 1,434 HCV RNA positive and 14,799 HCV negative controls). Demographics of the patients are listed in Table 1 . Patients with HCV antibody and RNA positive were significantly younger than control subjects. HCV seropositive patients had a significantly higher prevalence of traditional cardiovascular risk factors like hypertension, diabetes, obesity, and COPD. These co-morbidities were more frequent across both groups of patients with HCV seropositivity (antibody positive and RNA positive vs controls). Mean levels of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were significantly lower in the HCV cohort. As expected, patients with HCV had significantly elevated levels of markers of liver injury (aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, and alkaline phosphatase) compared with HCV negative patients.
| Characteristic | Hepatitis C Negative (n=14,799) | Hepatitis C Antibody Positive (n=8,251) | Hepatitis C RNA positive (n=1,434) | P value |
|---|---|---|---|---|
| Age (years) | 53.0 ± 16.1 | 47.3 ± 10.9 | 48.6 ± 9.7 | <0.001 |
| Male | 7992 (54.0 %) | 4641 (56.3 %) | 817 (57.0 %) | 0.002 |
| Female | 6807 (45.9 %) | 3610 (43.8 %) | 617 (43.0 %) | 0.002 |
| White | 8894 (60.1 %) | 6287 (76.2 %) | 1106 (77.1 %) | <0.001 |
| African American | 3507 (23.7 %) | 1526 (18.5 %) | 264 (18.4 %) | <0.001 |
| Others | 2398 (16.2 %) | 438 (5.3 %) | 64 (4.5 %) | <0.001 |
| Comorbidities | ||||
| Diabetes Mellitus | 755 (5.1%) | 924 (11.2 %) | 234 (16.3 %) | <0.001 |
| Obesity ∗ | 2486 (16.8 %) | 2385 (28.9 %) | 641 (44.7 %) | <0.001 |
| Chronic obstructive pulmonary disease | 266 (1.8 %) | 503 (6.1 %) | 92 (6.4 %) | <0.001 |
| Hypertension | 1805 (12.2 %) | 1898 (23.0 %) | 443 (30.9 %) | <0.001 |
| Incident CHD events | ||||
| Coronary Heart disease | 480 (3.2 %) | 387 (4.7 %) | 84 (5.9 %) | <0.001 |
| Liver Function † | ||||
| Albumin (mg/dl) | 5.5 ± 4.3 (1985) | 4.0 ± 2.6 (2485) | 3.7 ± 1.4 (846) | <0.001 |
| ALP (IU/L) | 87.2 ± 56.3 (3455) | 105.9 ± 88.7 (4257) | 96.9 ± 48.3 (1203) | <0.001 |
| ALT (IU/L) | 37.5± 129.3 (3406) | 74.0 ± 141.0 (4275) | 91.0 ± 149.0 (1212) | <0.001 |
| AST (IU/L) | 40.7 ± 165.9 (3629) | 88.0 ± 282.0 (4341) | 88.8 ± 134.5 (1217) | <0.001 |
| GGT (IU/L) | 64.0 ± 128.8 (2989) | 112.6 ± 165.1 (3822) | 104.4 ± 137.6 (1017) | <0.001 |
| Bilirubin (mg/dl) | 0.9 ± 1.4 (3216) | 1.7 ± 3.6 (4175) | 1.4 ± 1.7 (1202) | <0.001 |
| Lipid Profile † | ||||
| HDL-C (mg/dl) | 47.3 ± 16.2 (2655) | 42.6 ± 19.3 (1093) | 43.0 ± 19.7 (226) | <0.001 |
| LDL-C (mg/dl) | 107.7 ± 50.9 (1995) | 94.0 ± 40.6 (1968) | 87.0 ± 35.9 (520) | <0.001 |
| Cholesterol (mg/dl) | 185.8 ± 49.7 (2858) | 164.2 ± 63.0 (1169) | 156.5 ± 55.7 (245) | <0.001 |
| Triglycerides (mg/dl) | 163.3 ± 329.8 (2802) | 148.1 ± 178.0 (1323) | 138.8 ± 105.0 (411) | 0.10 |
| Creatinine (mg/dl) | 1.11 ± 0.95 (5440) | 1.13 ± 1.16 (4429) | 1.03 ± 1.09 (1163) | 0.01 |
| HbA1c (mg/dl) | 6.9 ± 2.0 (1308) | 7.0 ± 2.2 (602) | 6.6 ± 2.2 (214) | 0.06 |
∗ Obesity was defined as body mass index > 29.5.
† Data presented as mean ± SD; number of observations in parentheses.
There were a total of 951 patients with documented CHD (per ICD codes), of which 471 were HCV positive and 480 were negative for HCV. There were 84 patients with CHD in the HCV RNA positive cohort and 387 patients in the HCV antibody positive cohort. Patients with HCV positivity (groups a and b together) had a higher incidence of CHD events compared with controls (4.9% vs 3.2%, p <0.001). Furthermore, patients with detectable HCV RNA had a significantly higher incidence of CHD events compared with patients who were only HCV antibody positive with no detectable RNA (5.9% vs 4.7%, p = 0.04).
In a univariate analysis, age >50 years, male gender, hypertension, diabetes, obesity, COPD, HCV Ab positivity and HCV RNA positivity were associated with an increased risk of incident CHD. After adjusting for age and gender, all the previously mentioned conditions including HCV antibody and RNA positivity were significant risk factors for CHD ( Table 2 ). In a multivariate logistic regression analysis after adjusting for age, gender, hypertension, diabetes, and COPD, HCV Ab and RNA positivity were independent risk factors for CHD. The odds ratio for developing a CHD event was 1.32 (1.09 to 1.59, p <0.001) in the HCV antibody positive group and 1.59 (1.13 to 2.26, p <0.001) in the HCV RNA positive group ( Table 3 ). There was a significant interaction between HCV positivity and obesity as competing risk factors for CHD in the HCV positive population. Obese patients in the HCV cohort had lower odds of incident CHD compared with nonobese HCV RNA positive patients ( Table 3 ).
